Water soluble complexes of the antiviral drugs, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine and acyclovir: the role of hydrophobicity in complex formation

• Published in: Journal of pharmaceutical sciences Vol. 75; no. 7; p. 648
• Main Authors: Kenley, R A, Jackson, S E, Winterle, J S, Shunko, Y, Visor, G C
• Format: Journal Article
• Language: English
• Published: United States 01-07-1986
• Subjects: Acyclovir - analogs & derivatives; Acyclovir - analysis; Chemical Phenomena; Chemistry, Physical; Ganciclovir; Guanine - analysis; Guanosine - analysis; Solubility; Water
• ISSN: 0022-3549
• DOI: 10.1002/jps.2600750706

We investigated water-soluble complexes of various ligands with the antiviral drugs, 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) and 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG). For comparison, we also examined the "parent" compounds, guanine and guanosine, as substrates for complex formation. Using the phase-solubility technique, we measured formation constant (K1) values at 23 degrees C in pH 7 buffer. For a single substrate, formation constants with different ligands varied in the order: caffeine greater than pyridoxine approximately cytidine greater than nicotinamide greater than sucrose. With caffeine as the ligand, formation constants with different substrates varied in the order: guanine greater than guanosine approximately acyclovir greater than DHPG. The largest formation constant observed was 58 M-1 (for guanine-caffeine), and the smallest formation constant was 0.29 M-1 (for DHPG-sucrose). Examining the literature for formation constant data on compounds related to DHPG, and comparing literature data with our own, reveals a significant correlation between formation constants and ligand hydrophobicity. For 41 substrate-ligand pairs, least squares linear regression analysis of log K1 values versus various parameters reflecting donor-acceptor abilities (e.g., substrate and ligand HOMO and LUMO values, or substrate oxidation potentials) failed to significantly correlate. We conclude that ligand hydrophobicity is a general determinant of water soluble complex formation, but not necessarily the exclusive or dominant controlling factor for all complexes. Charge-transfer interactions are not important determinants of complex formation for the substrate-ligand combinations that we have considered.